Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan

ABSTRACT

Dosage forms, drug delivery systems, and methods related to sustained release of dextromethorphan or improved therapeutic effects are disclosed. Typically, bupropion or a related compound is orally administered to a human being to be treated with, or being treated with, dextromethorphan.

SUMMARY

Some embodiments include an oral sustained release delivery system fordextromethorphan, comprising bupropion or a prodrug thereof,dextromethorphan, and a water soluble vehicle.

Some embodiments include a method of decreasing the number of doses ofdextromethorphan that can be administered without loss of efficacy,comprising orally administering an effective amount of bupropion or athereof to a human being in need of treatment with dextromethorphan.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, isadministered on the first day of at least two days of treatment withdextromethorphan, wherein a decrease in the dextrorphan plasma leveloccurs on the first day that hydroxybupropion, or a prodrug thereof, anddextromethorphan are co-administered, as compared to the same amount ofdextromethorphan administered without hydroxybupropion or a prodrugthereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan to ahuman being in need of treatment with dextromethorphan, wherein thebupropion is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that bupropion and dextromethorphanare co-administered, as compared to the same amount of dextromethorphanadministered without bupropion.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the erythrohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that erythrohydroxybupropion, or aprodrug thereof, and dextromethorphan are co-administered, as comparedto the same amount of dextromethorphan administered withouterythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the threohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that threohydroxybupropion, or aprodrug thereof, and dextromethorphan are co-administered, as comparedto the same amount of dextromethorphan administered withoutthreohydroxybupropion or a prodrug thereof.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least eight consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the eighth day, the dextrorphanplasma level is lower than the dextrorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without hydroxybupropion, or aprodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without erythrohydroxybupropion,or a prodrug thereof, for eight consecutive days.

Some embodiments include a method of decreasing dextrorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least eight consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on theeighth day, the dextrorphan plasma level is lower than the dextrorphanplasma level that would have been achieved by administering the sameamount of dextromethorphan administered without threohydroxybupropion,or a prodrug thereof, for eight consecutive days.

Antidepressant compounds, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, can be used to improve thetherapeutic properties, such as in the treatment of neurologicaldisorders, of dextromethorphan. Bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, regardless of stereochemistry, can beeffective in inhibiting or reducing the metabolism of dextromethorphanin some human beings. This may be accomplished by co-administeringbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan.

Some embodiments include a method of treating a neurological disordercomprising administering an antidepressant compound and dextromethorphanto a human being in need thereof, wherein the human being is anextensive metabolizer of dextromethorphan.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering bupropion with dextromethorphan to the humanbeing.

Some embodiments include a method of inhibiting the metabolism ofdextromethorphan, comprising administering bupropion to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as bupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering bupropion to a human beingin need of treatment with dextromethorphan, wherein the human being isan extensive metabolizer of dextromethorphan, and whereindextromethorphan is present in the body of the human being at the sametime as bupropion.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering bupropion to a human being inneed thereof.

In some embodiments, an excess of one stereoisomer of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be administered. Inother embodiments, an excess of the S-enantiomer (includingenantiomerically pure S-enantiomer) or an excess of the R-enantiomer(including enantiomerically pure R-enantiomer) of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds may be administered.

In some embodiments, both dextromethorphan and bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, ametabolite, or prodrug of any of these compounds are formulated toimmediate release, and in other embodiments both bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, ametabolite or prodrug of any of these compounds are formulated to besustained release.

Some embodiments include a method of improving the antitussiveproperties of dextromethorphan comprising administering bupropion inconjunction with administration of dextromethorphan to a human being inneed of treatment for cough.

Some embodiments include a method of treating cough comprisingadministering a combination of bupropion and dextromethorphan to a humanbeing in need thereof.

Some embodiments include a method of treating a neurological disordercomprising administering bupropion and dextromethorphan to a human beingin need thereof, wherein the bupropion and dextromethorphan areadministered at least once a day for at least 8 days.

Some embodiments include a method of treating a neurological disordercomprising administering about 150 mg/day to about 300 mg/day ofbupropion and about 15 mg/day to about 60 mg/day of dextromethorphan toa human being in need thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering hydroxybupropion, or a prodrug thereof, withdextromethorphan to the human being.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering erythrohydroxybupropion, or a prodrugthereof, with dextromethorphan to the human being.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being in need of treatment with dextromethorphan,wherein the human being is an extensive metabolizer of dextromethorphan,comprising co-administering threohydroxybupropion, or a prodrug thereof,with dextromethorphan to the human being.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering bupropion to a human being,wherein the human being is an extensive metabolizer of dextromethorphan,and wherein dextromethorphan is present in the body of the human beingat the same time as bupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time ashydroxybupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering erythrohydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time aserythrohydroxybupropion.

Some embodiments include a method of inhibiting metabolism ofdextromethorphan, comprising administering threohydroxybupropion, or aprodrug thereof, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time asthreohydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as hydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering erythrohydroxybupropion,or a prodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as erythrohydroxybupropion.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, comprising administering threohydroxybupropion, ora prodrug thereof, to a human being in need of treatment withdextromethorphan, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as threohydroxybupropion.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan to ahuman being in need of treatment with dextromethorphan, wherein thebupropion is administered on the first day of at least two days ofco-administration of bupropion with dextromethorphan, wherein anincrease in the dextromethorphan plasma level occurs on the first daythat bupropion and dextromethorphan are co-administered, as compared tothe same amount of dextromethorphan administered without bupropion.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, isadministered on the first day of at least two days of co-administrationof hydroxybupropion, or a prodrug thereof, with dextromethorphan,wherein an increase in the dextromethorphan plasma level occurs on thefirst day that hydroxybupropion, or a prodrug thereof, anddextromethorphan are co-administered, as compared to the same amount ofdextromethorphan administered without hydroxybupropion or a prodrugthereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the erythrohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days ofco-administration of erythrohydroxybupropion, or a prodrug thereof, withdextromethorphan, wherein an increase in the dextromethorphan plasmalevel occurs on the first day that erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan are co-administered, as compared to thesame amount of dextromethorphan administered withouterythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need of treatment withdextromethorphan, wherein the threohydroxybupropion, or a prodrugthereof, is administered on the first day of at least two days ofco-administration of threohydroxybupropion, or a prodrug thereof, withdextromethorphan, wherein an increase in the dextromethorphan plasmalevel occurs on the first day that threohydroxybupropion, or a prodrugthereof, and dextromethorphan are co-administered, as compared to thesame amount of dextromethorphan administered withoutthreohydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least five consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the fifth day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouthydroxybupropion, or a prodrug thereof, for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouterythrohydroxybupropion, or a prodrug thereof, for five consecutivedays.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutthreohydroxybupropion, or a prodrug thereof, for five consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering bupropion and dextromethorphan, forat least six consecutive days, to a human being in need of treatmentwith dextromethorphan, wherein, on the sixth day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering hydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouthydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withouterythrohydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of increasing dextromethorphan plasmalevels comprising co-administering threohydroxybupropion, or a prodrugthereof, and dextromethorphan, for at least six consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thesixth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutthreohydroxybupropion, or a prodrug thereof, for six consecutive days.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering bupropion withdextromethorphan to a human patient in need of treatment withdextromethorphan, wherein dextromethorphan has a plasma level 12 hoursafter co-administering bupropion with dextromethorphan that is at leasttwice the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering hydroxybupropion, or aprodrug thereof, with dextromethorphan to a human patient in need oftreatment with dextromethorphan, wherein dextromethorphan has a plasmalevel 12 hours after co-administering hydroxybupropion, or a prodrugthereof, with dextromethorphan that is at least twice the plasma levelthat would be achieved by administering the same amount ofdextromethorphan without hydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering erythrohydroxybupropion,or a prodrug thereof, with dextromethorphan to a human patient in needof treatment with dextromethorphan, wherein dextromethorphan has aplasma level 12 hours after co-administering erythrohydroxybupropion, ora prodrug thereof, with dextromethorphan that is at least twice theplasma level that would be achieved by administering the same amount ofdextromethorphan without erythrohydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing a trough effect ofdextromethorphan comprising, co-administering threohydroxybupropion, ora prodrug thereof, with dextromethorphan to a human patient in need oftreatment with dextromethorphan, wherein dextromethorphan has a plasmalevel 12 hours after co-administering threohydroxybupropion, or aprodrug thereof, with dextromethorphan that is at least twice the plasmalevel that would be achieved by administering the same amount ofdextromethorphan without threohydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering bupropion and dextromethorphan to a human patient inneed of dextromethorphan treatment, wherein the human patient is at riskof experiencing the adverse event as a result of being treated withdextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering hydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering erythrohydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by dextromethorphan, comprisingco-administering threohydroxybupropion, or a prodrug thereof, anddextromethorphan to a human patient in need of dextromethorphantreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with dextromethorphan.

Some embodiments include a method of reducing an adverse eventassociated with treatment by bupropion, comprising co-administeringdextromethorphan and bupropion to a human patient in need of bupropiontreatment, wherein the human patient is at risk of experiencing theadverse event as a result of being treated with bupropion.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering hydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering erythrohydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering threohydroxybupropion, or aprodrug thereof, to a human being in need thereof.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering bupropion in conjunction withadministration of dextromethorphan to a human being in need of treatmentfor cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering hydroxybupropion, or a prodrugthereof, in conjunction with administration of dextromethorphan to ahuman being in need of treatment for cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering erythrohydroxybupropion, or aprodrug thereof, in conjunction with administration of dextromethorphanto a human being in need of treatment for cough.

Some embodiments include a method of improving antitussive properties ofdextromethorphan comprising administering threohydroxybupropion, or aprodrug thereof, in conjunction with administration of dextromethorphanto a human being in need of treatment for cough.

Some embodiments include a method of treating cough comprisingadministering a combination of hydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating cough comprisingadministering a combination of erythrohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating cough comprisingadministering a combination of threohydroxybupropion, or a prodrugthereof, and dextromethorphan to a human being in need thereof.

Some embodiments include a method of treating a neurological disordercomprising administering bupropion and dextromethorphan to a human beingin need thereof, wherein the bupropion and dextromethorphan areadministered at least once a day for at least 8 days.

Some embodiments include a method of treating a neurological disordercomprising administering hydroxybupropion, or a prodrug thereof, anddextromethorphan to a human being in need thereof, wherein the bupropionand dextromethorphan are administered at least once a day for at least 8days.

Some embodiments include a method of treating a neurological disordercomprising administering erythrohydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof, wherein thebupropion and dextromethorphan are administered at least once a day forat least 8 days.

Some embodiments include a method of treating a neurological disordercomprising administering threohydroxybupropion, or a prodrug thereof,and dextromethorphan to a human being in need thereof, wherein thebupropion and dextromethorphan are administered at least once a day forat least 8 days.

Some embodiments include an oral sustained release delivery system fordextromethorphan, comprising bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any ofthese compounds, dextromethorphan, and a water soluble vehicle.

Some embodiments include a method of decreasing the number of doses ofdextromethorphan that can be administered without loss of efficacy,comprising orally administering an effective amount of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or aprodrug of any of these compounds, to a human being in need of treatmentwith dextromethorphan.

Some embodiments include a pharmaceutical composition, dosage form, ormedicament comprising a therapeutically effective amount ofdextromethorphan, a therapeutically effective amount of anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, and a pharmaceutically acceptableexcipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the mean plasma concentrations of dextromethorphanover time after dosing on Day 8 for subjects administereddextromethorphan alone or dextromethorphan and bupropion.

FIG. 2 depicts mean AUC₀₋₁₂ of dextromethorphan on Day 8 for subjectsadministered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 3 depicts mean AUC₀₋₂₄ of dextromethorphan on Day 8 for subjectsadministered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 4 depicts mean AUC_(0-inf) of dextromethorphan on Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 5 depicts the fold changes in AUCs of dextromethorphan on Day 8 forsubjects administered dextromethorphan alone as compared todextromethorphan and bupropion.

FIG. 6 depicts mean AUC₀₋₁₂ of dextromethorphan on Day 1 and Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 7 depicts mean dextromethorphan trough plasma concentrations forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

FIG. 8 depicts mean dextromethorphan maximum plasma concentrations onDay 1 and Day 8 for subjects administered dextromethorphan alone ordextromethorphan and bupropion.

FIG. 9 is a plot of the mean plasma concentrations of dextrorphan overtime after dosing on Day 8 for subjects administered dextromethorphanalone or dextromethorphan and bupropion.

FIG. 10 depicts mean dextrorphan maximum plasma concentrations on Day 1and Day 8 for subjects administered dextromethorphan alone ordextromethorphan and bupropion.

FIG. 11 depicts mean AUC₀₋₁₂ of dextrorphan on Day 1 and Day 8 forsubjects administered dextromethorphan alone or dextromethorphan andbupropion.

DETAILED DESCRIPTION

Some embodiments include a method of treating neurological disorderscomprising administering a therapeutically effective amount ofdextromethorphan and a therapeutically effective amount of anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, to a person in need thereof.

Some embodiments include a method of enhancing the therapeuticproperties of dextromethorphan in treating neurological disorders,comprising co-administering dextromethorphan and an antidepressant, suchas bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

Some embodiments include a method of increasing dextromethorphan plasmalevels in a human being that is an extensive metabolizer ofdextromethorphan, comprising co-administering an antidepressantcompound, such as bupropion, and dextromethorphan to the human being.

Some embodiments include a method of inhibiting the metabolism ofdextromethorphan, comprising administering an antidepressant compound,such as bupropion, to a human being, wherein the human being is anextensive metabolizer of dextromethorphan, and wherein dextromethorphanis present in the body of the human being at the same time as theantidepressant.

Some embodiments include a method of increasing the metabolic lifetimeof dextromethorphan, including increasing the elimination half life(T_(1/2)) of dextromethorphan. These embodiments may compriseadministering an antidepressant compound, such as bupropion, to a humanbeing, wherein the human being is an extensive metabolizer ofdextromethorphan, and wherein dextromethorphan is present in the body ofthe human being at the same time as the antidepressant compound.

Some embodiments include a method of correcting extensive metabolism ofdextromethorphan, comprising administering an antidepressant compound,such as bupropion, to a human being in need thereof, such as a humanbeing in need of treatment for pain.

Some embodiments include a method of improving the therapeuticproperties of dextromethorphan in treating neurological disorderscomprising administering an antidepressant compound, such as bupropion,in conjunction with administration of dextromethorphan to a human beingin need of treatment for a neurological disorder.

Some embodiments include a method of treating neurological disorderscomprising administering a combination of an antidepressant compound,such as bupropion, and dextromethorphan to a human being in needthereof.

Dextromethorphan has the structure shown below.

Dextromethorphan is used as a cough suppressant. According to the FDA'sdextromethorphan product labeling requirement under the OTC Monograph[21CFR341.74], dextromethorphan should be dosed 6 times a day (every 4hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).

Dextromethorphan is rapidly metabolized in the human liver. This rapidhepatic metabolism may limit systemic drug exposure in individuals whoare extensive metabolizers. Human beings can be: 1) extensivemetabolizers of dextromethorphan—those who rapidly metabolizedextromethorphan; 2) poor metabolizers of dextromethorphan—those whoonly poorly metabolize dextromethorphan; or 3) intermediate metabolizersof dextromethorphan—those whose metabolism of dextromethorphan issomewhere between that of an extensive metabolizer and a poormetabolizer. Extensive metabolizers can also be ultra-rapidmetabolizers. Extensive metabolizers of dextromethorphan are asignificant portion of the human population. Dextromethorphan can, forexample, be metabolized to dextrorphan.

When given the same oral dose of dextromethorphan, plasma levels ofdextromethorphan are significantly higher in poor metabolizers orintermediate metabolizers as compared to extensive metabolizers ofdextromethorphan. The low plasma concentrations of dextromethorphan canlimit its clinical utility as a single agent for extensive metabolizers,and possibly intermediate metabolizers, of dextromethorphan. Someantidepressants, such as bupropion, inhibit the metabolism ofdextromethorphan, and can thus improve its therapeutic efficacy.Similarly, antidepressants may allow dextromethorphan to be given lessoften, such as once a day instead of twice a day, once a day instead ofthree times a day, once a day instead of four times a day, twice a dayinstead of three times a day, or twice a day instead of four times aday, without loss of therapeutic efficacy.

Pain or other neurological disorders may be treated by a methodcomprising administering a therapeutically effective amount ofdextromethorphan and a therapeutically effective amount of anantidepressant compound, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, to a person in need thereof.

Examples of neurological disorders that may be treated, or that may betreated with increased efficacy, by a combination of dextromethorphanand an antidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, include, but are not limited to:affective disorders, psychiatric disorders, cerebral function disorders,movement disorders, dementias, motor neuron diseases, neurodegenerativediseases, seizure disorders, and headaches.

Affective disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, include, but are notlimited to, depression, major depression, treatment-resistant depressionand treatment-resistant bipolar depression, bipolar disorders includingcyclothymia, seasonal affective disorder, mania, anxiety disorders,attention deficit disorder (ADD), attention deficit disorder withhyperactivity (ADDH), and attention deficit/hyperactivity disorder(AD/HD), bipolar and manic conditions, obsessive-compulsive disorder,bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome,premenstrual syndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression may be manifested by changes in mood, feelings of intensesadness, despair, mental slowing, loss of concentration, pessimisticworry, agitation, and self-deprecation. Physical symptoms of depressionmay include insomnia, anorexia, weight loss, decreased energy andlibido, and abnormal hormonal circadian rhythms.

Psychiatric disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, include, but are notlimited to, anxiety disorders, including but not limited to, phobias,generalized anxiety disorder, social anxiety disorder, panic disorder,agoraphobia, obsessive-compulsive disorder, and post-traumatic stressdisorder (PTSD); mania, manic depressive illness, hypomania, unipolardepression, depression, stress disorders, somatoform disorders,personality disorders, psychosis, schizophrenia, delusional disorder,schizoaffective disorder, schizotypy, aggression, aggression inAlzheimer's disease, agitation, and agitation in Alzheimer's disease.

Substance addiction abuse that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, includes, but is notlimited to, drug dependence, addiction to cocaine, psychostimulants(e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids,anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines,hallucinogens, phencyclidine, volatile solvents, and volatile nitrites.Nicotine addiction includes nicotine addiction of all known forms, suchas smoking cigarettes, cigars and/or pipes, and addiction to chewingtobacco.

Cerebral function disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, disorders involving intellectual deficits such as seniledementia, Alzheimer's type dementia, memory loss, amnesia/amnesticsyndrome, epilepsy, disturbances of consciousness, coma, lowering ofattention, speech disorders, voice spasms, Parkinson's disease,Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, andschizophrenia. Cerebral function disorders also include disorders causedby cerebrovascular diseases including, but not limited to, stroke,cerebral infarction, cerebral bleeding, cerebral arteriosclerosis,cerebral venous thrombosis, head injuries, and the like where symptomsinclude disturbance of consciousness, senile dementia, coma, lowering ofattention, and speech disorders.

Movement disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, akathisia, akinesia, associated movements, athetosis,ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea,Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia,tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis,dopamine-responsive dystonia, Parkinson's disease, restless legssyndrome (RLS), tremor, essential tremor, and Tourette's syndrome, andWilson's disease.

Dementias that may be treated by a combination of dextromethorphan andan antidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds include, but are not limited to,Alzheimer's disease, Parkinson's disease, vascular dementia, dementiawith Lewy bodies, mixed dementia, fronto-temporal dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington'sdisease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, amyotrophic lateral sclerosis (ALS), progressive bulbarpalsy, primary lateral sclerosis (PLS), progressive muscular atrophy,post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motoratrophies, Tay-Sach's disease, Sandoff disease, and hereditary spasticparaplegia.

Neurodegenerative diseases that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to Alzheimer's disease, prion-related diseases, cerebellarataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA),bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewybody disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS orLou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy,Shy-Drager syndrome, corticobasal degeneration, progressive supranuclearpalsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebralautosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Toothdisease (CMT), familial spastic paraparesis, neurofibromatosis,olivopontine cerebellar atrophy or degeneration, striatonigraldegeneration, Guillain-Barré syndrome, and spastic paraplesia.

Seizure disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, epileptic seizures, nonepileptic seizures, epilepsy, febrileseizures; partial seizures including, but not limited to, simple partialseizures, Jacksonian seizures, complex partial seizures, and epilepsiapartialis continua; generalized seizures including, but not limited to,generalized tonic-clonic seizures, absence seizures, atonic seizures,myoclonic seizures, juvenile myoclonic seizures, and infantile spasms;and status epilepticus.

Types of headaches that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, but are notlimited to, migraine, tension, and cluster headaches.

Other neurological disorders that may be treated by a combination ofdextromethorphan and an antidepressant such as bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds include, Rett Syndrome,autism, tinnitus, disturbances of consciousness disorders, sexualdysfunction, intractable coughing, narcolepsy, cataplexy; voicedisorders due to uncontrolled laryngeal muscle spasms, including, butnot limited to, abductor spasmodic dysphonia, adductor spasmodicdysphonia, muscular tension dysphonia, and vocal tremor; diabeticneuropathy, chemotherapy-induced neurotoxicity, such as methotrexateneurotoxicity; incontinence including, but not limited, stress urinaryincontinence, urge urinary incontinence, and fecal incontinence; anderectile dysfunction.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may be used to treat pain,pseudobulbar affect, depression (including treatment resistantdepression), disorders related to memory and cognition, schizophrenia,Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett'ssyndrome, seizures, cough (including chronic cough), etc.

In some embodiments, a combination of dextromethorphan and anantidepressant such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds may be used to treat dermatitis.

Pain relieving properties of dextromethorphan may be enhanced by amethod comprising co-administering dextromethorphan and anantidepressant, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, with dextromethorphan.

Pain relieving properties of bupropion may be enhanced by a methodcomprising co-administering dextromethorphan with bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds.

These methods may be used to treat, or provide relief to, any type ofpain including, but not limited to, musculoskeletal pain, neuropathicpain, cancer-related pain, acute pain, nociceptive pain, etc.

Examples of musculoskeletal pain include low back pain (i.e. lumbosacralpain), primary dysmenorrhea, and arthritic pain, such as pain associatedwith rheumatoid arthritis, juvenile rheumatoid arthritis,osteoarthritis, axial spondyloarthritis including ankylosingspondylitis, etc.

In some embodiments, a combination of dextromethorphan and anantidepressant, such as bupropion, is used to treat chronicmusculoskeletal pain.

Examples of neuropathic pain include diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, central pain, etc. Other causes of neuropathic paininclude cancer-related pain, lumbar nerve root compression, spinal cordinjury, post-stroke pain, central multiple sclerosis pain,HIV-associated neuropathy, and radio- or chemo-therapy associatedneuropathy, etc.

The term “treating” or “treatment” includes the diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals,or any activity that otherwise affects the structure or any function ofthe body of man or other animals.

Any antidepressant may be used in combination with dextromethorphan toimprove the therapeutic properties of dextromethorphan. Dextromethorphanand the antidepressant compound may be administered in separatecompositions or dosage forms, or may be administered in a singlecomposition or dosage form comprising both.

Antidepressant compounds that can be co-administered withdextromethorphan include, but are not limited to, bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion,clomipramine, doxepin, fluoxetine, mianserin, imipramine,2-chloroimipramine, amitriptyline, amoxapine, desipramine,protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine,isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram,sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine,venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone,selegiline, sibutramine, milnacipran, tesofensine, brasofensine,moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone,butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol,norfluoxetine, dapoxetine, etc., or a metabolite or prodrug of any ofthese compounds, or a pharmaceutically acceptable salt of any of thesecompounds.

Bupropion has the structure shown below (bupropion hydrochloride formshown).

Combining bupropion with dextromethorphan may provide greater efficacy,such as greater pain relief, than would otherwise be achieved byadministering either component alone. In extensive metabolizers,dextromethorphan can be rapidly and extensively metabolized, yieldinglow systemic exposure even at high doses. Bupropion, besides possessinganti-depressant and analgesic properties, is an inhibitor ofdextromethorphan metabolism. Metabolites of bupropion, which includehydroxybupropion, threohydroxybupropion (also known asthreohydrobupropion or threodihydrobupropion), anderythrohydroxybupropion (also known as erythrohydrobupropion orerythrodihydrobupropion), are also inhibitors of dextromethorphanmetabolism. Thus, bupropion, including a form of bupropion that israpidly converted in the body (such as a salt, hydrate, solvate,polymorph, etc.), is a prodrug of hydroxybupropion,threohydroxybupropion, and erythrohydroxybupropion.

As explained above, this inhibition may augment dextromethorphan plasmalevels, resulting in additive or synergistic efficacy such as relief ofneurological disorders including pain, depression, smoking cessation,etc. Thus, while inhibition of dextromethorphan metabolism is only oneof many potential benefits of the combination, co-administration ofdextromethorphan with bupropion may thereby enhance the efficacy ofbupropion for many individuals. Co-administration of dextromethorphanwith bupropion may enhance the analgesic properties of bupropion formany individuals. Co-administration of dextromethorphan with bupropionmay also enhance the antidepressant properties of bupropion for manyindividuals, including faster onset of action.

Another potential benefit of co-administration of dextromethorphan andbupropion is that it may be useful to reduce the potential for anadverse event, such as somnolence, associated with treatment bydextromethorphan. This may be useful, for example, in human patients atrisk of experiencing the adverse event as a result being treated withdextromethorphan.

Another potential benefit of co-administration of dextromethorphan andbupropion is that it may be useful to reduce the potential for anadverse event, such as seizure, associated with treatment by bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds. This may be useful, forexample, in human patients at risk of experiencing the adverse event asa result being treated with bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

With respect to dextromethorphan, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, co-administration may reduce acentral nervous system adverse event, a gastrointestinal event, oranother type of adverse event associated with any of these compounds.Central nervous system (CNS) adverse events include, but are not limitedto, nervousness, dizziness, sleeplessness, light-headedness, tremor,hallucinations, convulsions, CNS depression, fear, anxiety, headache,increased irritability or excitement, tinnitus, drowsiness, dizziness,sedation, somnolence, confusion, disorientation, lassitude,incoordination, fatigue, euphoria, nervousness, insomnia, sleepingdisturbances, convulsive seizures, excitation, catatonic-like states,hysteria, hallucinations, delusions, paranoia, headaches and/ormigraine, and extrapyramidal symptoms such as oculogyric crisis,torticollis, hyperexcitability, increased muscle tone, ataxia, andtongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea,vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominaldistension, flatulence, peptic ulcers with bleeding, loose stools,constipation, stomach pain, heartburn, gas, loss of appetite, feeling offullness in stomach, indigestion, bloating, hyperacidity, dry mouth,gastrointestinal disturbances, and gastric pain.

Co-administering dextromethorphan and an antidepressant, such asbupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, does not necessarily require that the two compounds beadministered in the same dosage form. For example, the two compounds maybe administered in a single dosage form, or they may be administered intwo separate dosage forms. Additionally, the two compounds may beadministered at the same time, but this is not required. The compoundscan be given at different times as long as both are in a human body atthe same time for at least a portion of the time that treatment byco-administration is being carried out.

In some embodiments, co-administration of a combination of bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, and dextromethorphanresults in both bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan contributing to the pain relievingproperties of the combination. For example, the combination may haveimproved pain relieving properties as compared to bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, alone or compared todextromethorphan alone, including potentially faster onset of action.

In some embodiments, the combination may have improved pain relievingproperties of at least about 0.5%, at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%,about 10% to about 20%, about 20% to about 30%, about 30% to about 40%,about 40% to about 50%, about 50% to about 60%, about 60% to about 70%,about 70% to about 80%, about 80% to about 90%, about 90% to about 100%,about 100% to about 110%, about 110% to about 120%, about 120% to about130%, about 130% to about 140%, about 140% to about 150%, about 150% toabout 160%, about 160% to about 170%, about 170% to about 180%, about180% to about 190%, about 190% to about 200%, or any amount of painrelief in a range bounded by, or between, any of these values, ascompared to bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, alone.

In some embodiments, the combination may have improved pain relievingproperties of at least about 0.5%, at least about 1%, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%,about 10% to about 20%, about 20% to about 30%, about 30% to about 40%,about 40% to about 50%, about 50% to about 60%, about 60% to about 70%,about 70% to about 80%, about 80% to about 90%, about 90% to about 100%,about 100% to about 110%, about 110% to about 120%, about 120% to about130%, about 130% to about 140%, about 140% to about 150%, about 150% toabout 160%, about 160% to about 170%, about 170% to about 180%, about180% to about 190%, about 190% to about 200%, or any amount of painrelief in a range bounded by, or between, any of these values, ascompared to as compared to dextromethorphan alone.

Unless otherwise indicated, any reference to a compound herein, such asdextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, by structure, name, or any other means, includespharmaceutically acceptable salts; alternate solid forms, such aspolymorphs, solvates, hydrates, etc.; tautomers; deuterium modifiedcompounds, such as deuterium modified dextromethorphan; or any chemicalspecies that may rapidly convert to a compound described herein underconditions in which the compounds are used as described herein.

Examples of deuterium modified dextromethorphan include, but are notlimited to, those shown below.

A dosage form or a composition may be a blend or mixture ofdextromethorphan and a compound that inhibits the metabolism ofdextromethorphan, such as bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, either alone or within a vehicle. Forexample, dextromethorphan and bupropion may be dispersed within eachother or dispersed together within a vehicle. A dispersion may include amixture of solid materials wherein small individual particles aresubstantially one compound, but the small particles are dispersed withinone another, such as might occur if two powders of two different drugsare blended with a solid vehicle material, and the blending is done inthe solid form. In some embodiments, dextromethorphan and bupropion maybe substantially uniformly dispersed within a composition or dosageform. Alternatively, dextromethorphan and bupropion may be in separatedomains or phases within a composition or dosage form. For example, onedrug may be in a coating and another drug may be in a core within thecoating. For example, one drug may be formulated for sustained releaseand another drug may be formulated for immediate release.

Some embodiments include administration of a tablet that containsbupropion in a form that provides sustained release and dextromethorphanin a form that provides immediate release. While there are many waysthat sustained release of bupropion may be achieved, in some embodimentsbupropion is combined with hydroxypropyl methylcellulose. For example,particles of bupropion hydrochloride could be blended withmicrocrystalline cellulose and hydroxypropyl methylcellulose (e.g.,METHOCEL®) to form an admixture of blended powders. This could then becombined with immediate release dextromethorphan in a single tablet.

Dextromethorphan and/or an antidepressant, such as bupropion,hydroxybupropion, threohydroxybupropion and erythrohydroxybupropion, ora non-bupropion antidepressant (all of which are referred tocollectively herein as “therapeutic compounds” for convenience) may becombined with a pharmaceutical carrier selected on the basis of thechosen route of administration and standard pharmaceutical practice asdescribed, for example, in Remington's Pharmaceutical Sciences, 2005.The relative proportions of active ingredient and carrier may bedetermined, for example, by the solubility and chemical nature of thecompounds, chosen route of administration and standard pharmaceuticalpractice.

Therapeutic compounds may be administered by any means that may resultin the contact of the active agent(s) with the desired site or site(s)of action in the body of a patient. The compounds may be administered byany conventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. For example, they may be administeredas the sole active agents in a pharmaceutical composition, or they canbe used in combination with other therapeutically active ingredients.

Therapeutic compounds may be administered to a human patient in avariety of forms adapted to the chosen route of administration, e.g.,orally or parenterally. Parenteral administration in this respectincludes administration by the following routes: intravenous,intramuscular, subcutaneous, intraocular, intrasynovial, transepithelialincluding transdermal, ophthalmic, sublingual and buccal; topicallyincluding ophthalmic, dermal, ocular, rectal and nasal inhalation viainsufflation, aerosol and rectal systemic.

The ratio of dextromethorphan to bupropion may vary. In someembodiments, the weight ratio of dextromethorphan to bupropion may beabout 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or anyratio in a range bounded by, or between, any of these values. A ratio of0.1 indicates that the weight of dextromethorphan is 1/10 that ofbupropion. A ratio of 10 indicates that the weight of dextromethorphanis 10 times that of bupropion.

The amount of dextromethorphan in a therapeutic composition may vary.For example, some liquid compositions may comprise about 0.0001% (w/v)to about 50% (w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% toabout 10% (w/v), about 0.001% (w/v) to about 1% (w/v), about 0.1% (w/v)to about 0.5% (w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) toabout 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) toabout 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) toabout 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) toabout 40% (w/v), or about 40% (w/v) to about 50% (w/v) ofdextromethorphan.

Some liquid dosage forms may contain about 10 mg to about 500 mg, about30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mgto about 50 mg, about 80 mg to about 100 mg, about 110 mg to about 130mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg,about 120 mg, or about 180 mg of dextromethorphan, or any amount ofdextromethorphan in a range bounded by, or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan.

Some solid dosage forms may contain about 10 mg to about 500 mg, about30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mgto about 70 mg, about 80 mg to about 100 mg, about 110 mg to about 130mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120mg, or about 180 mg of dextromethorphan, or any amount ofdextromethorphan in a range bounded by, or between, any of these values.

The amount of bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, in a therapeutic composition may vary. If increasing theplasma level of dextromethorphan is desired, bupropion,hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or ametabolite or prodrug of any of these compounds, should be administeredin an amount that increases the plasma level of dextromethorphan. Forexample, bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, may be administered in an amount that results in a plasmaconcentration of dextromethorphan in the human being, on day 8, that isat least about 2 times, at least about 5 times, at least about 10 times,at least about 15 times, at least about 20 times, at least about 30times, at least about 40 times, at least about 50 times, at least about60 times, at least about 70 times, or at least about 80 times, theplasma concentration of the same amount of dextromethorphan administeredwithout bupropion, hydroxybupropion, erythrohydroxybupropion,threohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

In some embodiments, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may administered to a human being inan amount that results in a 12 hour area under the curve from the timeof dosing (AUC₀₋₁₂), or average plasma concentration in the human beingfor the 12 hours following dosing (C_(avg)) of dextromethorphan, on day8, that is at least about 2 times, at least about 5 times, at leastabout 10 times, at least about 15 times, at least about 20 times, atleast about 30 times, at least about 40 times, at least about 50 times,at least about 60 times, at least about 70 times, or at least about 80times the plasma concentration of the same amount of dextromethorphanadministered without bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds, may administered to a human being inan amount that results in a maximum plasma concentration (C_(max)) ofdextromethorphan in the human being, on day 8, that is at least about 2times, at least about 5 times, at least about 10 times, at least about15 times, at least about 20 times, at least about 30 times, or at leastabout 40 times the plasma concentration of the same amount ofdextromethorphan administered without bupropion, hydroxybupropion,erythrohydroxybupropion, threohydroxybupropion, or a metabolite orprodrug of any of these compounds.

For co-administration of bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, an increase in the dextromethorphanplasma level can occur on the first day that bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, is administered, ascompared to the same amount of dextromethorphan administered withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite of prodrug of any of thesecompounds. For example, the dextromethorphan plasma level on the firstday that bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least about 1.5 times, at leastabout at least 2 times, at least about 2.5 times, at least about 3times, at least about 4 times, at least about 5 times, at least about 6times at least about 7 times, at least about 8 times, at least about 9times, or at least about 10 times the level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds.

In some embodiments, the dextromethorphan AUC on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least twice the AUC that would beachieved by administering the same amount of dextromethorphan withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

In some embodiments, the dextromethorphan C_(max) on the first day thatbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered may be at least twice the C_(max) that wouldbe achieved by administering the same amount of dextromethorphan withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds.

In some embodiments, the dextromethorphan trough level (e.g., plasmalevel 12 hours after administration) on the first day that bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, is administered may beat least twice the trough level that would be achieved by administeringthe same amount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, is administered on the first day of at least two days oftreatment with dextromethorphan, wherein a decrease in the dextrorphanplasma level occurs on the first day that bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, and dextromethorphan areco-administered, as compared to the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds. For example, the dextrorphan plasma level on the first daymay be reduced by at least 5% as compared to the dextrorphan plasmalevel that would be achieved by administering the same amount ofdextromethorphan without bupropion.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, are co-administered for at least five consecutive days, to ahuman being in need of treatment with dextromethorphan, wherein, on thefifth day, the dextromethorphan plasma level is higher than thedextromethorphan plasma level that would have been achieved byadministering the same amount of dextromethorphan administered withoutbupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite of prodrug of any of thesecompounds, for five consecutive days. For example, the dextromethorphanplasma level on the fifth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be at least 5 times, atleast 10 times, at least 20 times, at least 40 times, at least 50 times,at least 60 times, at least 65 times, or up to about 500 times, thelevel that would be achieved by administering the same amount ofdextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for five consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least sixconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the sixth day, the dextromethorphan plasmalevel is higher than the dextromethorphan plasma level that would havebeen achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for six consecutive days. For example, the dextromethorphanplasma level on the sixth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be at least 5 times, atleast 10 times, at least 20 times, at least 30 times, at least 50 times,at least 60 times, at least 70 times, at least 75 times, or up to about500 times, the level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for six consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least sevenconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the seventh day, the dextromethorphanplasma level is higher than the dextromethorphan plasma level that wouldhave been achieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for seven consecutive days. For example, the dextromethorphanplasma level on the seventh day (for example at 0 hours, 1 hour, 3hours, 6 hours, or 12 hours after administration) may be at least 5times, at least 10 times, at least 20 times, at least 30 times, at least50 times, at least 70 times, at least 80 times, at least 90 times, or upto about 500 times, the level that would be achieved by administeringthe same amount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for seven consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan, are co-administered for at least eightconsecutive days, wherein, on the eighth day, dextromethorphan has aplasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12hours, after co-administering bupropion with dextromethorphan that is atleast 5 times, at least 10 times, at least 20 times, at least 30 times,at least 50 times, at least 60 times, at least 70 times, at least 80times, at least 90 times, at least 100 times, or up to about 1,000times, the plasma level that would be achieved by administering the sameamount of dextromethorphan without bupropion, hydroxybupropion,threohydroxybupropion, erythrohydroxybupropion, or a metabolite orprodrug of any of these compounds, for eight consecutive days.

In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, and dextromethorphan are co-administered for at least eightconsecutive days, to a human being in need of treatment withdextromethorphan, wherein, on the eighth day, the dextrorphan plasmalevel is lower than the dextrorphan plasma level that would have beenachieved by administering the same amount of dextromethorphanadministered without bupropion, hydroxybupropion, threohydroxybupropion,erythrohydroxybupropion, or a metabolite or prodrug of any of thesecompounds, for eight consecutive days. For example, the dextrorphanplasma level on the eighth day (for example at 0 hours, 1 hour, 3 hours,6 hours, or 12 hours after administration) may be reduced by at least10%, at least 20%, at least 30%, at least 40%, or at least 50%, ascompared to the dextrorphan plasma level that would be achieved byadministering the same amount of dextromethorphan without bupropion,hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or ametabolite or prodrug of any of these compounds, for eight consecutivedays.

In some embodiments, bupropion may be administered to a human being inan amount that results in an AUC₀₋₁₂ of bupropion in the human being, onday 8, that is at least about 100 ng·hr/mL, at least about 200 ng·hr/mL,at least about 500 ng·hr/mL, at least about 600 ng·hr/mL, at least about700 ng·hr/mL, at least about 800 ng·hr/mL, at least about 900 ng·hr/mL,at least about 1,000 ng·hr/mL, at least about 1,200 ng·hr/mL, at least1,600 ng·hr/mL, or up to about 15,000 ng·hr/mL.

In some embodiments, bupropion may be administered to a human being inan amount that results in a C_(avg) of bupropion in the human being, onday 8, that is at least about 10 ng/mL, at least about 20 ng/mL, atleast about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL,at least about 70 ng/mL, at least about 80 ng/mL, at least about 90ng/mL, at least about 100 ng/mL, at least 120 ng/mL, or up to about1,500 ng/mL.

In some embodiments, bupropion may be administered to a human being inan amount that results in a C_(max) of bupropion in the human being, onday 8, that is at least about 10 ng/mL, at least about 20 ng/mL, atleast about 50 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL,at least about 110 ng/mL, at least about 120 ng/mL, at least about 130ng/mL, at least about 140 ng/mL, at least 200 ng/mL, or up to about1,500 ng/mL.

Some liquid compositions may comprise about 0.0001% (w/v) to about 50%(w/v), about 0.01% (w/v) to about 20% (w/v), about 0.01% to about 10%(w/v), about 1% (w/v) to about 3% (w/v), about 3% (w/v) to about 5%(w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15%(w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15%(w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30%(w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about50% (w/v) of bupropion, or any amount of bupropion in a range boundedby, or between, any of these values.

Some liquid dosage forms may contain about 10 mg to about 1000 mg, about50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg toabout 200 mg, about 110 mg to about 140 mg, about 180 mg to about 220mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about300 mg of bupropion, or any amount of bupropion in a range bounded by,or between, any of these values.

Some solid compositions may comprise at least about 5% (w/w), at leastabout 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), atleast about 70% (w/w), at least about 80%, about 10% (w/w) to about 30%(w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30%(w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40%(w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80%(w/w), about 50% (w/w) to about 60% (w/w), about 70% (w/w) to about 80%(w/w), or about 80% (w/w) to about 90% (w/w) of bupropion, or any amountof bupropion in a range bounded by, or between, any of these values.

Some solid dosage forms may contain about 10 mg to about 1000 mg, about50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg toabout 200 mg, about 110 mg to about 140 mg, about 50 mg to about 150 mg,about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200mg, about 150 mg, or about 300 mg of bupropion, or any amount ofbupropion in a range bounded by, or between, any of these values.

In some embodiments, bupropion is administered at a dose that results ina bupropion plasma level of about 0.1 μM to about 10 μM, about 0.1 μM toabout 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM, about 0.2μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5 μM, about 2μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5 μM to about 2μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3 μM, about 1.8μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma level in arange bounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, is administered at a dose that results in ahydroxybupropion plasma level of about 0.1 μM to about 10 μM, about 0.1μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM,about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or anyplasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in an AUC₀₋₁₂ of hydroxybupropion in the human being, on day 8,that is at least about 3,000 ng·hr/mL, at least about 7,000 ng·hr/mL, atleast about 10,000 ng·hr/mL, at least about 15,000 ng·hr/mL, at leastabout 20,000 ng·hr/mL, at least about 30,000 ng·hr/mL, up to about50,000 ng·hr/mL, up to about 150,000 ng·hr/mL, or any AUC in a rangebounded by, or between, any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in a C_(max) of hydroxybupropion in the human being, on day 8,that is at least about 300 ng/mL, at least about 700 ng/mL, at leastabout 1,000 ng/mL, at least about 1,500 ng/mL, at least about 2,000ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about50,000 ng/mL, or any C_(max) in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug ofhydroxybupropion, may be administered to a human being in an amount thatresults in a C_(avg) of hydroxybupropion in the human being, on day 8,that is at least about 200 ng/mL, at least about 300 ng/mL, at leastabout 700 ng/mL, at least about 1,000 ng/mL, at least about 1,500 ng/mL,at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about10,000 ng/mL, up to about 50,000 ng/mL, or any C_(avg) in a rangebounded by, or between, any of these values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, is administered at a dose that results in athreohydroxybupropion plasma level of about 0.1 μM to about 10 μM, about0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about 1 μM,about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM to about 5μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM, about 1.5μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM to about 3μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or anyplasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in an AUC₀₋₁₂ of threohydroxybupropion in the human being,on day 8, that is at least about 1,000 ng·hr/mL, at least about 2,000ng·hr/mL, at least about 4,000 ng·hr/mL, at least about 5,000 ng·hr/mL,at least about 8,000 ng·hr/mL, up to about 10,000 ng·hr/mL, up to about40,000 ng·hr/mL, or any AUC in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in a C_(max) of threohydroxybupropion in the human being,on day 8, that is at least about 100 ng/mL, at least about 200 ng/mL, atleast about 400 ng/mL, at least about 500 ng/mL, at least about 600ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about10,000 ng/mL, or any C_(max) in a range bounded by, or between, any ofthese values.

In some embodiments, bupropion, threohydroxybupropion, or a prodrug ofthreohydroxybupropion, may be administered to a human being in an amountthat results in a C_(avg) of threohydroxybupropion in the human being,on day 8, that is at least about 100 ng/mL, at least about 300 ng/mL, atleast about 400 ng/mL, at least about 600 ng/mL, at least about 800ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any C_(avg)in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, is administered at a dose that results in anerythrohydroxybupropion plasma level of about 0.1 μM to about 10 μM,about 0.1 μM to about 5 μM, about 0.2 μM to about 3 μM, 0.1 μM to about1 μM, about 0.2 μM to about 2 μM, 1 μM to about 10 μM, about 1 μM toabout 5 μM, about 2 μM to about 3 μM, or about 2.8 μM to about 3 μM,about 1.5 μM to about 2 μM, about 4.5 μM to about 5 μM, about 2.5 μM toabout 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, orany plasma level in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in an AUC₀₋₁₂ of erythrohydroxybupropion in thehuman being, on day 8, that is at least about 200 ng·hr/mL, at leastabout 400 ng·hr/mL, at least about 700 ng·hr/mL, at least about 1,000ng·hr/mL, at least about 1,500 ng·hr/mL, at least about 3,000 ng·hr/mL,up to about 5,000 ng·hr/mL, up to about 30,000 ng·hr/mL, or any plasmalevel in a range bounded by, or between, any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in a C_(max) of erythrohydroxybupropion in the humanbeing, on day 8, that is at least about 30 ng/mL, at least about 60ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up toabout 1,000 ng/mL, or any C_(max) in a range bounded by, or between, anyof these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug oferythrohydroxybupropion, may be administered to a human being in anamount that results in a C_(avg) of erythrohydroxybupropion in the humanbeing, on day 8, that is at least about 20 ng/mL, at least about 30ng/mL, at least about 50 ng/mL, at least about 80 ng/mL, at least about90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at leastabout 200 ng/mL, at least about 300 ng/mL, up to about 1,000 ng/mL, upto about 5,000 ng/mL, or any C_(avg) in a range bounded by, or between,any of these values.

For compositions comprising both dextromethorphan and bupropion, someliquids may comprise about 0.0001% (w/v) to about 50% (w/v), about 0.01%(w/v) to about 20% (w/v), about 0.01% to about 10% (w/v), about 1% (w/v)to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) toabout 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) toabout 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) toabout 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) toabout 40% (w/v), about 40% (w/v) to about 50% (w/v) of dextromethorphanand bupropion combined, or any amount in a range bounded by, or between,any of these values. Some solid compositions may comprise at least about5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at leastabout 50% (w/w), at least about 70% (w/w), at least about 80%, about 10%(w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20%(w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30%(w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50%(w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 70%(w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) ofdextromethorphan and bupropion combined, or any amount in a rangebounded by, or between, any of these values. In some embodiments, theweight ratio of dextromethorphan to bupropion in a single composition ordosage form may be about 0.1 to about 2, about 0.2 to about 1, about 0.1to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4,about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, orbetween, any of these values.

A therapeutically effective amount of a therapeutic compound may varydepending upon the circumstances. For example, a daily dose ofdextromethorphan may in some instances range from about 0.1 mg to about1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg,about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mgto about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg,about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg toabout 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg,about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg toabout 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg toabout 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg,about 240 mg, about 360 mg, or any daily dose in a range bounded by, orbetween, any of these values. Dextromethorphan may be administered oncedaily; or twice daily or every 12 hours, three times daily, four timesdaily, or six times daily in an amount that is about half, one third,one quarter, or one sixth, respectively, of the daily dose.

A daily dose of bupropion, may in some instances range from about 10 mgto about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg toabout 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about200 mg about 300 mg, about 300 mg to about 400 mg, about 400 mg to about500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg,about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600mg, or any daily dose in a range bounded by, or between, any of thesevalues. Bupropion may be administered once daily; or twice daily orevery 12 hours, or three times daily in an amount that is about half orone third, respectively, of the daily dose.

In some embodiments: 1) about 50 mg/day to about 100 mg/day, about 100mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about150 mg/day to about 200 mg/day, about 200 mg/day to about 250 mg/day,about 250 mg/day to about 300 mg/day of bupropion, or about 300 mg/dayto about 500 mg/day of bupropion; and/or 2) about 15 mg/day to about 60mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100mg/day, about 80 mg/day to about 110 mg/day, about 100 mg/day to about150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan,are administered to a human being in need thereof.

In some embodiments, about 150 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 90 mg/dayof dextromethorphan, about 150 mg/day of bupropion and about 120 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 90 mg/dayof dextromethorphan, about 200 mg/day of bupropion and about 120 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 30 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 60 mg/dayof dextromethorphan, about 300 mg/day of bupropion and about 90 mg/dayof dextromethorphan, or about 300 mg/day of bupropion and about 120mg/day of dextromethorphan is administered to the human being.

In some embodiments, about 100 mg/day of bupropion and about 15 mg/dayof dextromethorphan is administered to the human being for 1, 2, or 3days, followed by about 200 mg/day of bupropion and about 30 mg/day ofdextromethorphan. In some embodiments, about 100 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor 1, 2, or 3 days, followed by about 200 mg/day of bupropion and about60 mg/day of dextromethorphan.

In some embodiments, about 75 mg/day of bupropion and about 15 mg/day ofdextromethorphan is administered to the human being for 1, 2, or 3 days,followed by about 150 mg/day of bupropion and about 30 mg/day ofdextromethorphan. In some embodiments, about 75 mg/day of bupropion andabout 30 mg/day of dextromethorphan is administered to the human beingfor 1, 2, or 3 days, followed by about 150 mg/day of bupropion and about60 mg/day of dextromethorphan.

An antidepressant compound, such as bupropion, may be administered foras long as needed to treat a neurological condition, such as pain,depression or cough. In some embodiments, an antidepressant compound,such as bupropion, and dextromethorphan are administered at least once aday, such as once daily or twice daily, for at least 1 day, at least 3days, at least 5 days, at least 7 days, at least 8 days, at least 14days, at least 30 days, at least 60 days, at least 90 days, at least 180days, at least 365 days, or longer.

Therapeutic compounds may be formulated for oral administration, forexample, with an inert diluent or with an edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, compressed intotablets, or incorporated directly with the food of the diet. For oraltherapeutic administration, the active compound may be incorporated withan excipient and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch, or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acid,and the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose, or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

Therapeutic compounds may be formulated for parental or intraperitonealadministration. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also have an oil dispersed within, or dispersed in, glycerol, liquidpolyethylene glycols, and mixtures thereof. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

Specifically Contemplated Embodiments

The following are examples of embodiments that are specificallycontemplated by the inventor:

-   Embodiment 1. A method of treating pain or a neurological disorder    comprising administering a therapeutically effective amount of    dextromethorphan and a therapeutically effective amount of an    antidepressant compound, to a person in need thereof.-   Embodiment 2. A method of treating pain comprising administering a    combination of an antidepressant compound and dextromethorphan to a    human being in need thereof.-   Embodiment 3. A method of enhancing the pain relieving properties of    dextromethorphan, comprising co-administering dextromethorphan and    an antidepressant compound.-   Embodiment 4. A method of increasing dextromethorphan plasma levels    in a human being that is an extensive metabolizer of    dextromethorphan, comprising co-administering an antidepressant    compound to the human being receiving a treatment that includes    administration of dextromethorphan.-   Embodiment 5. A method of inhibiting the metabolism of    dextromethorphan, comprising administering an antidepressant    compound to a human being, wherein the human being is an extensive    metabolizer of dextromethorphan, and wherein dextromethorphan is    present in the body of the human being at the same time as the    antidepressant compound.-   Embodiment 6. A method of increasing the metabolic lifetime of    dextromethorphan, comprising administering an antidepressant    compound to a human being, wherein the human being is an extensive    metabolizer of dextromethorphan, and wherein dextromethorphan is    present in the body of the human being at the same time as the    antidepressant compound.-   Embodiment 7. A method of correcting extensive metabolism of    dextromethorphan, comprising administering an antidepressant    compound to a human being in need thereof.-   Embodiment 8. A method of improving pain relieving properties of    dextromethorphan comprising administering an antidepressant compound    in conjunction with administration of dextromethorphan to a human    being in need of treatment for pain.-   Embodiment 9. A method of improving antitussive properties of    dextromethorphan comprising administering an antidepressant compound    in conjunction with administration of dextromethorphan to a human    being in need of treatment for cough.-   Embodiment 10. A method of treating cough comprising administering a    combination of an antidepressant compound and dextromethorphan to a    human being in need thereof.-   Embodiment 11. A method of improving a therapeutic property of    dextromethorphan comprising administering an antidepressant compound    in conjunction with administration of dextromethorphan to a human    being in need of treatment for a neurological disorder.-   Embodiment 12. A method of treating a neurological disorder    comprising administering a combination of an antidepressant compound    and dextromethorphan to a human being in need thereof.-   Embodiment 13. A method of treating a neurological disorder    comprising administering an antidepressant compound and    dextromethorphan to a human being in need thereof, wherein the human    being is an extensive metabolizer of dextromethorphan.-   Embodiment 14. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, or 13, wherein the dextromethorphan and the    antidepressant compound are administered in separate dosage forms.-   Embodiment 15. A pharmaceutical composition comprising a    therapeutically effective amount of dextromethorphan, a    therapeutically effective amount of an antidepressant compound, and    a pharmaceutically acceptable excipient.-   Embodiment 16. An oral dosage form comprising at least 20 mg of    dextromethorphan and an effective amount of an antidepressant    compound to inhibit the metabolism of dextromethorphan in a human    being that is an extensive metabolizer of dextromethorphan.-   Embodiment 17. The oral dosage form of embodiment 16, wherein about    30 mg to about 350 mg of dextromethorphan is present in the dosage    form.-   Embodiment 18. The oral dosage form of embodiment 16 or 17, wherein    about 100 mg to about 400 mg of bupropion is present in the dosage    form.-   Embodiment 19. The oral dosage form of any of embodiments 16, 17, or    18, comprising an amount of bupropion that results in a bupropion    plasma level of about 0.1 μM to about 10 μM when the oral dosage    form is administered to a human being.-   Embodiment 20. The oral dosage form of embodiment 19, comprising an    amount of bupropion that results in a bupropion plasma level of    about 0.1 μM to about 2 μM when the oral dosage form is administered    to a human being.-   Embodiment 21. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, or 13, wherein bupropion is administered at a dose that    results in a bupropion plasma level of about 0.1 μM to about 10 μM.-   Embodiment 22. The method of embodiment 21, wherein bupropion is    administered at a dose that results in a bupropion plasma level of    about 0.3 μM to about 1 μM.-   Embodiment 23. The method, composition, or dosage form of any of    embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,    or 17, wherein the antidepressant compound is bupropion or a    metabolite thereof.-   Embodiment 24. The method, composition, or dosage form of any of    embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,    or 17, wherein the antidepressant compound is bupropion.-   Embodiment 25. The method, composition, or dosage form of embodiment    1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17,    wherein the antidepressant compound is clomipramine, doxepin,    fluoxetine, mianserin, imipramine, 2-chloroimipramine,    amitriptyline, amoxapine, desipramine, protriptyline, trimipramine,    nortriptyline, maprotiline, phenelzine, isocarboxazid,    tranylcypromine, paroxetine, trazodone, citalopram, sertraline,    aryloxy indanamine, benactyzine, escitalopram, fluvoxamine,    venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone,    selegiline, or a pharmaceutically acceptable salt thereof-   Embodiment 26. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 11,    12, 13, 14, 21, 22, 23, 24, or 25, wherein dextromethorphan is    administered to the human being for the treatment of cough.-   Embodiment 27. A method of treating a neurological disorder    comprising administering about 150 mg/day to about 300 mg/day of    bupropion and about 30 mg/day to about 120 mg/day of    dextromethorphan to a human being in need thereof.-   Embodiment 28. A method of treating a neurological disorder    comprising administering bupropion and dextromethorphan to a human    being in need thereof, wherein the bupropion and dextromethorphan    are administered at least once a day for at least 8 days.-   Embodiment 29. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, or 27, wherein bupropion    is administered to the human being at least daily for at least 8    days.-   Embodiment 30. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, or 28, wherein    dextromethorphan is administered to the human being at least daily    for at least 8 days.-   Embodiment 31. The method of embodiment 28, 29, or 30, wherein    bupropion is administered in an amount that results in a plasma    concentration of dextromethorphan in the human being, on day 8, that    is at least 10 times the plasma concentration of the same amount of    dextromethorphan administered without bupropion.-   Embodiment 32. The method of embodiment 28, 29, 30, or 31, wherein    bupropion is administered in an amount that results in an AUC₀₋₁₂ of    hydroxybupropion, on day 8, that is at least about 3000 ng·hr/mL.-   Embodiment 33. The method of embodiment 28, 29, 30, 31, or 32,    wherein bupropion is administered in an amount that results in an    AUC₀₋₁₂ of erythrohydroxybupropion, on day 8, that is at least about    400 ng·hr/mL.-   Embodiment 34. The method of embodiment 28, 29, 30, 31, 32, or 33,    wherein bupropion is administered in an amount that results in an    AUC₀₋₁₂ of threohydroxybupropion, on day 8, that is at least about    2000 ng·hr/mL.-   Embodiment 35. The method, composition, or dosage form of embodiment    1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,    20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein    the weight ratio of dextromethorphan to bupropion is about 0.1 to    about 0.5.-   Embodiment 36. The method of embodiment 27, 28, 29, 30, 31, 32, 33,    34, or 35, wherein the human being is an extensive metabolizer of    dextromethorphan.-   Embodiment 37. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,    33, 34, 35, or 36, wherein about 150 mg/day of bupropion and about    30 mg/day of dextromethorphan is administered to the human being.-   Embodiment 38. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,    33, 34, 35, or 36, wherein about 150 mg/day of bupropion and about    60 mg/day of dextromethorphan is administered to the human being.-   Embodiment 39. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,    33, 34, 35, or 36, wherein about 200 mg/day of bupropion and about    30 mg/day of dextromethorphan is administered to the human being.-   Embodiment 40. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,    33, 34, 35, or 36, wherein about 100 mg/day of bupropion and about    15 mg/day of dextromethorphan is administered to the human being for    about 1 to about 3 days, followed by about 200 mg/day of bupropion    and about 30 mg/day of dextromethorphan.-   Embodiment 41. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,    33, 34, 35, or 36, wherein about 200 mg/day of bupropion and about    60 mg/day of dextromethorphan is administered to the human being.-   Embodiment 42. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,    10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,    33, 34, 35, or 36, wherein about 100 mg/day of bupropion and about    30 mg/day of dextromethorphan is administered to the human being for    about 1 to about 3 days, followed by about 200 mg/day of bupropion    and about 60 mg/day of dextromethorphan.-   Embodiment 43. The method of embodiment 4, 5, 6, 7, 9, 10, 11, 12,    13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,    36, 37, 38, 39, 40, 41, or 42, wherein dextromethorphan is    administered to the human being for the treatment of pain.-   Embodiment 44. The method of embodiment 43, wherein the pain    comprises postoperative pain, cancer pain, arthritic pain,    lumbosacral pain, musculoskeletal pain, central multiple sclerosis    pain, nociceptive pain, or neuropathic pain.-   Embodiment 45. The method of embodiment 43, wherein the pain    comprises musculoskeletal pain, neuropathic pain, cancer-related    pain, acute pain, or nociceptive pain.-   Embodiment 46. The method of embodiment 43, wherein the pain    comprises postoperative pain.-   Embodiment 47. The method of embodiment 43, wherein the pain    comprises cancer pain.-   Embodiment 48. The method of embodiment 43, wherein the pain    comprises arthritic pain.-   Embodiment 49. The method of embodiment 43, wherein the pain    comprises lumbosacral pain.-   Embodiment 50. The method of embodiment 43, wherein the pain    comprises musculoskeletal pain.-   Embodiment 51. The method of embodiment 43, wherein the pain    comprises neuropathic pain.-   Embodiment 52. The method of embodiment 43, wherein the pain    comprises nociceptive pain.-   Embodiment 53. The method of embodiment 43, wherein the pain    comprises chronic musculoskeletal pain.-   Embodiment 54. The method of embodiment 43, wherein the pain is    associated with rheumatoid arthritis.-   Embodiment 55. The method of embodiment 43, wherein the pain is    associated with juvenile rheumatoid arthritis.-   Embodiment 56. The method of embodiment 43, wherein the pain is    associated with osteoarthritis.-   Embodiment 57. The method of embodiment 43, wherein the pain is    associated with an axial spondyloarthritis.-   Embodiment 58. The method of embodiment 43, wherein the pain is    associated with ankylosing spondylitis.-   Embodiment 59. The method of embodiment 43, wherein the pain is    associated with diabetic peripheral neuropathy.-   Embodiment 60. The method of embodiment 43, wherein the pain is    associated with post-herpetic neuralgia.-   Embodiment 61. The method of embodiment 43, wherein the pain is    associated with trigeminal neuralgia.-   Embodiment 62. The method of embodiment 43, wherein the pain is    associated with monoradiculopathies.-   Embodiment 63. The method of embodiment 43, wherein the pain is    associated with phantom limb pain.-   Embodiment 64. The method of embodiment 43, wherein the pain is    associated with central pain.-   Embodiment 65. The method of embodiment 43, wherein the pain    comprises cancer-related pain.-   Embodiment 66. The method of embodiment 43, wherein the pain is    associated with lumbar nerve root compression.-   Embodiment 67. The method of embodiment 43, wherein the pain is    associated with spinal cord injury.-   Embodiment 68. The method of embodiment 43, wherein the pain is    associated with post-stroke pain.-   Embodiment 69. The method of embodiment 43, wherein the pain is    associated with central multiple sclerosis pain.-   Embodiment 70. The method of embodiment 43, wherein the pain is    associated with HIV-associated neuropathy.-   Embodiment 71. The method of embodiment 43, wherein the pain is    associated with radio-therapy associated neuropathy.-   Embodiment 72. The method of embodiment 43, wherein the pain is    associated with chemo-therapy associated neuropathy.-   Embodiment 73. The method of embodiment 43, wherein the pain    comprises dental pain.-   Embodiment 74. The method of embodiment 43, wherein the pain is    associated with primary dysmenorrhea.-   Embodiment 75. The method of embodiment 4, 5, 6, 7, 9, 10, 11, 12,    13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,    36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,    53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,    70, 71, 72, 73, or 74, wherein 90 mg/day of dextromethorphan is    administered to the human being.-   Embodiment 76. The method of embodiment 75, wherein 45 mg of    dextromethorphan is administered twice a day to the human being.-   Embodiment 77. The method of embodiment 75 or 76, wherein 150 mg/day    of bupropion is administered to the human being.-   Embodiment 78. The method of embodiment 75 or 76, wherein 180 mg/day    of bupropion is administered to the human being.-   Embodiment 79. The method of embodiment 75 or 76, wherein 200 mg/day    of bupropion is administered to the human being.-   Embodiment 80. The method of claim 123 or 124, wherein 300 mg/day of    bupropion is administered to the human being.

U.S. Provisional Application No. 61/900,354 is incorporated by referenceherein in its entirety. PCT Application No. PCT/US2014/64184 isincorporated by reference herein in its entirety

EXAMPLES Example 1

Fifteen human subjects were randomized into one of two treatment groupsreceiving either dextromethorphan (DM) alone, or DM in combination withbupropion, as shown in Table 1 below.

TABLE 1 Study Design Dose Levels Dura- Total Group Bupropion/DM DosingRegimen tion Subjects A  0 mg/60 mg DM: Twice daily, Days 8 Days 1-8 1-8B 150 mg/60 mg Bupropion: Once daily, Days 7 Days 1-3; Twice daily, 1-8Days 4-8 DM: Twice daily, Days 1-8

All subjects were extensive, including ultra-rapid, metabolizers ofdextromethorphan as determined by CYP2D6 genetic testing.Dextromethorphan was dosed at 12-hour intervals on Days 1-8, with afinal morning dose on Day 8. Bupropion was dosed once daily on Days 1-3,and at 12-hour intervals thereafter, with a final morning dose on Day 8.

Plasma samples were collected for concentration analysis ofdextromethorphan, total dextrorphan, bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8.Plasma samples for determination of trough concentrations ofdextromethorphan were obtained approximately 12 hours after dosing ondays 1, 5, 6, and 8.

Concentrations of dextromethorphan, total dextrorphan (unconjugated andglucuronide forms), bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion, were determinedusing LC-MS/MS. Pharmacokinetic parameters were calculated.

Phenotypic determination of dextromethorphan metabolizer status wasperformed by calculating the dextromethorphan/dextrorphan metabolicratio as described in Jurica et al. Journal of Clinical Pharmacy andTherapeutics, 2012, 37, 486-490. Plasma concentrations ofdextromethorphan and dextrorphan 3 hours after dosing were used, with adextromethorphan/dextrorphan ratio of 0.3 or greater indicating a poormetabolizer phenotype.

Results

Plasma concentrations of dextromethorphan were significantly increasedwith bupropion administration, as illustrated in FIG. 1 and Table 2.

TABLE 2 Mean Day 8 Dextromethorphan Plasma Concentrations (ng/mL) TimeDextromethorphan Dextromethorphan + (hours) (Group A) Bupropion (GroupB) 0 1.2 110.6 1 2.4 129.3 2 3.6 153.9 3 3.6 151.6 4 3.3 149.1 6 2.5150.0 8 1.9 144.4 12 1.1 119.3 24 0.4 95.3 36 0.1 69.0

The AUC of dextromethorphan was significantly increased withadministration of bupropion as show in FIGS. 2-4. As shown in FIG. 5,administration of bupropion with dextromethorphan resulted in anapproximately 60-fold, 80-fold, and 175-fold increase in meandextromethorphan AUC₀₋₁₂, AUC₀₋₂₄, and AUC_(0-inf), respectively on Day8 as compared to administration of dextromethorphan alone. As shown inFIG. 6, the increase in dextromethorphan AUC occurred as early as Day 1(an approximate 3-fold increase in AUC₀₋₁₂).

Trough plasma concentrations of dextromethorphan were significantlyincreased with administration of bupropion as illustrated in FIG. 7 andTable 3. Administration of bupropion with dextromethorphan resulted inan approximately 105-fold increase in mean trough plasma concentrationof dextromethorphan on Day 8 as compared to administration ofdextromethorphan alone.

Mean average plasma concentrations (C_(avg)) of dextromethorphan on Day8 increased approximately 60-fold with bupropion administration ascompared to administration of dextromethorphan alone. Maximum meanplasma concentrations (C_(max)) were also significantly increased asillustrated in FIG. 8.

TABLE 3 Mean Trough Dextromethorphan Plasma Concentrations (ng/mL)Dextromethorphan Dextromethorphan + Fold (Group A) Bupropion (Group B)Change Day 1 0.7 2.5 3.5 Day 5 1.2 80.9 70 Day 6 1.3 102.2 78 Day 7 1.2110.6 94 Day 8 1.1 119.3 105

The T_(max) and elimination half life (T_(1/2 el)) of dextromethorphanwere significantly increased with administration of bupropion on Day 8.The increase of T_(1/2 el) shows that the metabolic lifetime ofdextromethorphan was increased. Administration of bupropion withdextromethorphan resulted in a mean T_(max) of 3.6 hours, compared to2.3 hours for dextromethorphan alone. Administration of bupropion withdextromethorphan resulted in a mean T_(1/2 el) of 27.7 hours, comparedto 6.6 hours for dextromethorphan alone.

Plasma concentrations of dextrorphan were significantly decreased withbupropion administration, as illustrated in FIG. 9 and Table 4.

TABLE 4 Mean Day 8 Dextrorphan Plasma Concentrations (ng/mL) TimeDextromethorphan Dextromethorphan + (hours) (Group A) Bupropion (GroupB) 0 132.4 165.3 1 688.9 190.7 2 959.1 214.9 3 778.1 214.4 4 594.9 205.16 324.7 172.5 8 189.6 159.6 12 74.8 152.8 24 12.2 133.0 36 0.1 107.6

As shown in FIGS. 10-11, there was an approximate 78% reduction in meandextrorphan C_(max), and an approximate 55% reduction in meandextrorphan AUC₀₋₁₂ on Day 8 with administration of bupropion.

Phenotypic determination of dextromethorphan metabolizer status showedthat no subjects in either treatment arm were poor metabolizers onDay 1. On Day 8 however, 100% of subjects treated with bupropion hadconverted to poor metabolizer status as compared to 0% of subjectstreated with dextromethorphan alone. The mean plasmadextromethorphan/dextrorphan metabolic ratio increased from 0.01 on Day1 to 0.71 on Day 8 with bupropion administration. The mean ratio in thegroup administered DM alone was 0.00 on Day 1 and remained unchanged onDay 8.

On Day 8, average plasma concentrations of bupropion, hydroxybupropion,erythrohydroxybupropion, and threohydroxybupropion were at least 10ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively after bupropionadministration.

As used in this section, the term “fold change” or “fold increase”refers to the ratio of a value for bupropion with dextromethorphan tothe same value for dextromethorphan alone (i.e. the value for bupropionwith dextromethorphan divided by the same value for dextromethorphanalone).

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodin all instances as indicating both the exact values as shown and asbeing modified by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained. At the very least, and not asan attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorexpects skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise thanspecifically described herein. Accordingly, the claims include allmodifications and equivalents of the subject matter recited in theclaims as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof iscontemplated unless otherwise indicated herein or otherwise clearlycontradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

The invention claimed is:
 1. A method of increasing dextromethorphan plasma levels in a human being, comprising co-administering bupropion with about 40 mg to about 500 mg of dextromethorphan once a day or about 10 mg to about 300 mg of dextromethorphan twice a day to the human being for eight consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, and wherein on the eighth day that bupropion and dextromethorphan are co-administered, the co-administration results in an AUC₀₋₁₂ of dextromethorphan that is at least about 20 times the AUC₀₋₁₂ that would be achieved by administering the same amount of dextromethorphan without bupropion for eight consecutive days.
 2. The method of claim 1, wherein the AUC₀₋₁₂ of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 500 ng·hr/m L.
 3. The method of claim 1, wherein the AUC₀₋₁₂ of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is about 800 ng·hr/mL to about 900 ng·hr/mL.
 4. The method of claim 1, wherein the AUC₀₋₂₄ of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 600 ng·hr/mL.
 5. The method of claim 1, wherein the AUC_(0-inf) of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 1000 ng·hr/mL.
 6. The method of claim 1, wherein the AUC_(0-inf) of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered is at least about 2000 ng·hr/mL.
 7. The method of claim 1, wherein the C_(max) of dextromethorphan on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 10 ng/mL.
 8. The method of claim 1, wherein the C_(max) of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 40 ng/mL.
 9. The method of claim 1, wherein the C_(max) of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 60 ng/mL.
 10. The method of claim 1, wherein an excess of one stereoisomer of bupropion is administered.
 11. The method of claim 1, wherein an excess of the S-enantiomer of bupropion is administered.
 12. The method of claim 1, wherein an excess of the R-enantiomer of bupropion is administered.
 13. The method of claim 1, wherein about 160 mg to about 260 mg of bupropion per day is administered to the human being.
 14. The method of claim 1, wherein about 185 mg to about 235 mg of bupropion per day is administered to the human being.
 15. The method of claim 1, wherein about 40 mg to about 140 mg of dextromethorphan per day is administered to the human being.
 16. The method of claim 1, wherein about 65 mg to about 115 mg of dextromethorphan per day is administered to the human being.
 17. The method of claim 1, wherein about 200 mg to about 220 mg of bupropion and about 80 mg to about 100 mg of dextromethorphan is administered to the human being per day.
 18. The method of claim 1, wherein the bupropion and the dextromethorphan are administered in a single dosage form.
 19. The method of claim 1, wherein the bupropion is in a sustained-release formulation.
 20. The method of claim 17, wherein the bupropion is in a sustained release formulation and the dextromethorphan is in an immediate release formulation.
 21. The method of claim 18, wherein the bupropion is in a sustained-release formulation and the dextromethorphan is in an immediate-release formulation.
 22. A method of increasing exposure to dextromethorphan in a human being, comprising co-administering bupropion with about 40 mg to about 500 mg of dextromethorphan once a day in a single dosage form or about 10 mg to about 300 mg of dextromethorphan twice a day in a single dosage form to the human being for eight consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, and wherein on the eighth day that bupropion and dextromethorphan are co-administered, the co-administration results in an AUC₀₋₁₂ of dextromethorphan that is at least about 15 times the AUC₀₋₁₂ that would be achieved by administering the same amount of dextromethorphan without bupropion for eight consecutive days.
 23. The method of claim 22, wherein the AUC₀₋₁₂ of dextromethorphan, on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 500 ng·hr/m L.
 24. The method of claim 22, wherein the C_(max), of dextromethorphan on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 10 ng/mL.
 25. The method of claim 22, wherein the C_(avg) of dextromethorphan on the eighth day that bupropion and dextromethorphan are co-administered, is at least about 100 ng/mL.
 26. The method of claim 22, wherein an excess of one stereoisomer of bupropion is administered.
 27. The method of claim 22, wherein an excess of the S-enantiomer of bupropion is administered.
 28. The method of claim 22, wherein an excess of the R-enantiomer of bupropion is administered.
 29. The method of claim 22, wherein about 200 mg to about 220 mg of bupropion and about 80 mg to about 100 mg of dextromethorphan is administered to the human being per day.
 30. The method of claim 22, wherein the bupropion is in a sustained-release formulation and the dextromethorphan is in an immediate-release formulation. 